DEVELOPMENTAL CONTROL OF N-CAM EXPRESSION BY HOX AND PAX GENE-PRODUCTS

A mounting body of evidence suggests that cell-cell adhesion molecules (CAMs) play critical roles in morphogenetic patterning. Perturbations of CAM binding can lead to altered tissue pattern and interruption of tissue interactions can lead to altered patterns of CAM expression. These observations focus attention on the factors responsible for the place-dependent expression of adhesion molecules such as N-CAM, the neural cell adhesion molecule. Our recent experiments in vitro indicate that transcription factors encoded by Hox and Pax genes bind to specific DNA sequences in the N-CAM promoter and activate that promoter. In particular, a region of the N-CAM promoter designated the homeodomain binding site (HBS) interacts with a variety of different homeodomain proteins. A different region of the N-CAM promoter binds to the paired domain of Pax proteins. These transcription factors differentially regulate the N-CAM gene. Such in vitro studies suggest that the N-CAM gene may be an in vivo target for homeobox and Pax gene products. Recent experiments on transgenic mice carrying normal and mutated segments of the N-CAM promoter linked to a lacZ reporter gene suggest that the N-CAM regulation observed in vitro actually has counterparts in vivo. The significance of these observations is that they connect gene products capable of morphoregulation (such as CAMs) to pattern-forming genes.